Genetic Testing Is Providing New Hope for Babies Born with Mysterious Ailments

Within hours of entering the world, little Sebastiana Manuel’s entire body froze in a rigid spasm. Her neck twisted, her face turned blue, and one side of her body stiffened as if someone were yanking her violently. She screamed.

At first her doctor wasn’t too concerned; some newborns have seizures. But Sebastiana’s kept coming every few hours. And the way her arms and legs stiffened during each episode was unusual. When her mother Dolores Sebastian tried to breast-feed her, she wouldn’t eat. After the baby’s body convulsed more than a dozen times in her first night, an ambulance rushed her from the local hospital in Fallbrook, Calif., where she was born, to the only advanced-care children’s hospital in the area, Rady Children’s Hospital in San Diego.

But even the specialists there were baffled by Sebastiana’s symptoms. As doctors hooked up her brain to monitors and conducted test after test from her crib in the neonatal intensive care unit (NICU), Dolores and her husband Pascual Manuel couldn’t touch or hold their baby. The nurses used one of Dolores’ shirts as a pillow so Sebastiana could still smell her mother’s scent and know that she was there.

Hours later, they received devastating news from Dr. Jeffrey Gold, director of neonatal neurology at Rady and the University of California, San Diego. “He told us he wasn’t sure what was wrong with her, but he didn’t think she was going to make it,” says Dolores. “I cried and cried in the corner, and I tuned out the rest of what he said. I wanted to blame someone about why she was that way.”

Because Sebastiana’s brain scans were abnormal, Gold suspected that her brain was not fully developed, which could have triggered her seizures. Repeated seizures can interrupt a newborn’s brain from making all the right connections it needs to develop its myriad networks–for an immune system, digestive system, functioning brain, strong bones, growing muscles. Without those networks, babies can suffer from severe developmental disorders, and many don’t make it past their second birthday. Gold wanted to do an MRI the next day to be sure. In the worst case, he advised the Manuels, they would have to decide whether to allow doctors to insert tubes to help Sebastiana breathe and eat or let her die a natural death without them.

The Manuels prepared for the worst. Catholics from Guatemala, they didn’t want their daughter to die without being baptized, so they hurriedly arranged a ceremony in the NICU, with the priest and family surrounding Sebastiana’s crib.

But Sebastiana had one thing going for her. A year before she was born, Dr. Stephen Kingsmore launched a genomics institute at Rady designed to help babies like her. From any infant younger than 4 months who has a sickness that can’t be explained, Kingsmore’s team takes a vial of blood to run a genetic test. Within days, they sequence the entire genome of the baby, looking for clues to explain the undiagnosed symptoms and alert doctors to any abnormalities they see in the DNA.

On the basis of those results, which arrived six days after Sebastiana’s birth–and a few days after her baptism–Gold adjusted his initially dire prognosis. Sebastiana’s DNA told him that an antiseizure drug different from those that doctors normally use–one that is rarely used in infants–would be more effective at treating her seizures. The other drugs were making her sleepy, and if they were used for too long, her development could be slowed. The MRI showed that there wasn’t likely anything physically wrong with her brain, so if Gold controlled Sebastiana’s seizures, there was a chance it could develop normally. Once he made the switch, she became more alert, responding to her parents and eating as any healthy infant would. And her seizures stopped.

The genetic-testing program at Rady is still in the study phase, which means it’s not part of standard care for babies with mystery symptoms–yet. All the infants who have had their DNA mapped are part of a research trial. But so far, Kingsmore’s team has decoded the genomes of about 100 newborns with unexplained illnesses. Of those, about half had their symptoms explained with a proper diagnosis, and of those, 80% received life-changing treatments that doctors otherwise might never have considered. The power of using genetic testing in real time persuaded the Food and Drug Administration to allow Kingsmore’s group to report their results directly to doctors without the additional confirmation that the agency normally requires (which could take up to a week) if it would change the baby’s treatment. The National Institutes of Health (NIH) has supported Kingsmore’s work with a $6 million grant, and other doctors are starting to appreciate how useful genetic information can be. By the end of the year, 15 children’s hospitals across the country will start sending samples from their most challenging patients to Rady so that they too can make better decisions about how to diagnose and treat those patients.

If Kingsmore gets his way, mapping the DNA of these babies will one day be as standard as ordering a blood test. These infants often carry the answer to their own mystery illnesses in their very DNA; it’s just a matter of recognizing and reading the genetic clues. “If they don’t have a diagnosis, doctors are trying to hit a piñata with a blindfold on,” says Kingsmore. “All we’re trying to do is take the blindfold off.” The babies whose genomes Kingsmore is sequencing, including Sebastiana, are part of the NIH study to document how useful DNA mapping can be. With more babies and more genetic maps, he hopes to prove that smart genomic testing can save lives, which in turn will persuade not just doctors treating newborns but other physicians treating adults for nearly any disease to start thinking of their patients’ DNA as the next indispensable tool in medicine. It could pave the way for using genetics to diagnose and treat disease, and validate the power of personalized medicine. “His project is going to be a watershed,” says Dr. Tracy Trotter, chair of the council on genetics at the American Academy of Pediatrics. “When you see that it saves lives and it saves brains, when you are touched by that as a physician one time, you are forever interested.”

Kingsmore’s genetic operation is concentrated in a 2,700-sq.-ft. space on the second floor of one of Rady’s medical office buildings. An affable 57-year-old Irishman prone to sports analogies, he has a gentle lilt and warm demeanor that make him an apt advocate for babies. Previously, he led the Center for Pediatric Genomic Medicine at Children’s Mercy Hospital in Kansas City, Mo., where he pioneered a rapid genetic-sequencing program with the goal of providing real-time DNA information to doctors that would change treatments for the sickest babies.

Kingsmore still remembers the first child whose genome he mapped, which convinced him that genetic sequencing was needed in every children’s hospital. That 7-year-old girl had a genetic abnormality that could have been easily treated with a supplement found in pharmacies and supermarkets–for about 5¢ a dose. But the genetic testing was done too late, and the girl had already suffered from brain damage due to her condition, as had her younger sister. Had the genetic test been run when they were newborns, their brains might have been saved. “Those first cases made us realize, Holy cow, for the sake of 5¢, these children could have had a completely different outcome,” says Kingsmore. “That’s when I, and all of us, got really serious about this.”

But while he was adamant that genetic screening could help diagnose and treat newborns, not everyone in the medical community agreed that screening was mature enough for use in the daily care of patients. It costs about $8,500 to sequence a baby’s DNA, and no insurers then or now cover the test. Many experts still saw DNA sequencing as an experimental curiosity rather than a medical necessity. Ever since the human genome was mapped in 2001, the promise of using that trove of medical information has lured many a scientist and investor into ambitious ideas for making genome sequencing more routine. But doing sequencing right takes time. Commercial gene-testing companies often take up to six weeks to map a genome–far too long for newborns whose every breath is a struggle.

Frustrated, Kingsmore moved his operation to Rady in 2015. Ernest Rady, the Canadian-American financier and entrepreneur for whom the hospital is named, agreed with his vision and donated $120 million to create the Rady Children’s Institute for Genomic Medicine. To make his genetic testing more practical, Kingsmore has limited it to a very defined population of patients who could benefit: the sickest newborns in the NICU who don’t have a diagnosis. “These are little tiny babies looking for an excuse to die,” says Dr. Donald Kearns, CEO of Rady.

When Kingsmore maps the genomes, he doesn’t scan them randomly hoping that an answer will miraculously pop out. If the genome is like a person’s Internet of everything, then he uses a refined keyword search to extract only what he needs to know to explain a baby’s sickness. He’s not interested in whether that infant has a gene that makes her more likely to develop Alzheimer’s, for example. That laser-like focus is the key to finding the right answer for the right newborn.

When Kingsmore began his program, he created a custom database of the known symptoms and conditions that can affect babies; he now folds in commercial software that does the same. (“We’re a bit like pigs–we’ll eat anything,” he says of the scope of symptoms he scans.) Those symptoms are matched with whatever mutations scientists have described in studies and compared with the results of the sequencing. If there are no reported mutations fitting the symptoms, Kingsmore’s group documents the first case and provides the best treatment based on what they know. Genetic testing can provide a significant number of answers, but it can’t solve every mystery. Kingsmore is hoping that will soon change.

Elizabeth and Tristan Holbrook spend time with their newborn daughter Grace, Rady Children’s Hospital, San Diego, CA, July 18, 2017

John Francis Peters for TIME

Kingsmore holds the world record for fastest genetic diagnosis from mapping the human genome: 26 hours. In his lab, DNA decoding machines run nearly 24 hours a day, seven days a week. Even commercial sequencing companies can’t produce a map of a human genome as quickly. On average, it takes Kingsmore’s team 96 hours from the time a blood sample enters the lab to the time that the specific sequence of 3 billion base pairs unique to that person is churned out.

Mapping the genome is the easy part. Once the DNA is decoded, the real challenge lies in figuring out what it means. A small percentage of genetic mutations are associated with disease, while a much larger percentage make up so-called variants of unknown significance. These are the genetic changes that doctors don’t know how to decode yet. And they are the reason that many are still wary about ordering whole genome testing. “When you crunch a genome, you’re talking about 600 to 800 million data points, and in trying to analyze that, there are lots of gray zones,” says Dr. Eric Topol, director of the Scripps Translational Science Institute. “There is no magic Google search for the genome today.”

To address that problem, Kingsmore is intent on making the genomic information he generates useful to doctors and patients by making sure that every test is connected to a list of suggested treatments, if they’re available, that doctors can consider. “We need to break the artificial glass barrier where we think the genomics job is done if we print the report,” he says. “We’re not done until our babies have had a change of care or we’re convinced that they are getting the best care possible for their particular diagnosis.”

That’s what happened in Sebastiana’s case. The sequencing found a rare defect in a gene called KCNQ2. Aberrations in this gene can contribute to Ohtahara syndrome, which causes continued seizures. But depending on where the gene is mutated, the outcomes can be dramatically different. A mutation in one part of the gene can mean seizures in the first few months but no serious long-term consequences. Children with those mutations develop normally and live healthy lives as adults.

Mutations in another part of the gene, however, can cause persistent seizures that disrupt the development of the brain, leading to severe problems. “We worry about epilepsy, developmental delays, intellectual disability and cerebral palsy,” says Gold. About half these infants don’t make it past age 2.

Sebastiana had a mutation that was in neither of those regions. Hers was smack in the middle of the gene. There were no previous descriptions of her variant in case studies; it was a completely new mutation. Gold couldn’t tell the Manuels whether they could expect their daughter to outgrow her seizures or whether she would fail to develop like other newborns and continue to have seizures until her early death.

The genetic testing did tell him, however, that her mutation affected a particular pathway in her brain, and he knew there was a drug that could address that. It wasn’t an antiseizure drug doctors normally use in infants; still, with the genetic support, he felt confident it would control her seizures and hopeful that it would give her brain a chance to develop normally.

So far, it seems he was right. Sebastiana’s brain scans have improved considerably since her first ones. That means there’s a strong chance that she will not have the severe developmental delays that other children with Ohtahara syndrome experience. Sebastiana is a little slower to hit her milestones, such as holding up her head and crawling, but Gold is cautiously optimistic that her case may show how powerful genetic testing can be in diagnosing and treating seizures in newborns early, which could lead to better health outcomes for them. Three weeks after her emergency admission at Rady, she went home for the first time, on Christmas Day. “I thank God every night that I get to sleep with my daughter, that I get to cuddle her, and she doesn’t have tubes in her and she doesn’t have seizures,” says Dolores. Since she’s been home, Sebastiana has had only one seizure, but that might have been due to an unrelated respiratory infection.

These are the kinds of second chances that Kingsmore and his colleagues hope to continue to make by introducing genetic testing as early as possible to help newborns. “I do this because I am haunted by the kids we could have saved had we tested earlier,” says Dr. David Dimmock, medical director of the Rady Children’s Institute for Genomic Medicine.

Even when DNA mapping does not lead to a diagnosis or change in treatment, it can be valuable. For Liz and Tristan Holbrook, an accountant and software developer in San Diego, genetic sequencing of their first child, Grace, gave them much-needed clarity. Grace was born with a congenital hernia and heart condition that required two operations in her first four weeks. The Holbrooks agreed to get genetic testing to learn if DNA defects were causing Grace’s condition; the answers could help her treatment and their family planning. “If her condition was something we could pass on to future children, we might think differently about doing that,” says Liz. However, Grace’s DNA didn’t reveal anything out of the ordinary, indicating that the issues Grace faced wouldn’t affect future kids. “It was a big sigh of relief,” says Liz.

More doctors are seeing the value that genomics can provide. At Cincinnati Children’s Hospital Medical Center, physicians are launching a program that offers genetic sequencing to infants referred there for whatever reason as part of their medical workup–similar to the way doctors order a CT scan to learn more about a patient’s health. At the University of Michigan, doctors sequence a specific portion of children’s genomes to help guide treatment of those with undiagnosed diseases. And it’s not just infants who can benefit; as the testing expands, it may improve diagnosis and treatment of adults as well. “I would love to see genomic sequencing used more often,” says Dr. Jeffrey Innis, a pediatric geneticist at the University of Michigan.

Standing in the way are not just concerns about the practicality of genetic testing but also the cost. No insurers currently reimburse the expensive test. But Kingsmore’s strategy is to change the cost-benefit equation by proving through his studies that genetic sequencing for the sickest babies will save money in the long term, sparing them the expensive and lengthy medical care they will need if they remain undiagnosed or are treated with the wrong therapies. He estimates that genetic testing could save about $1 billion in annual NICU costs across the country.

For parents of babies who have benefited from the testing, it’s obviously priceless. “There is a reason why things happen,” says Pascual. “I think Sebastiana is here to educate our entire family to grow together and understand the basic blessing of life and to never forget it. She is a miracle.”